Proteins that behave as switches hold great promise as selective protein therapeutics. Previous studies by the PI have demonstrated that protein switches can be engineered by creating a large number of different fusions between two genes and subjecting these gene fusions to evolution in the lab. Such directed evolution strategies will be used to develop and improve protein switches to effectively activate prodrugs selectively in cancer cells. These switches will be evaluated for their ability to eliminate tumor xenographs in vivo using endogenous expression and via systemic delivery. These switches in combination with the appropriate prodrug have potential as a targeted therapeutic for the treatment of cancer.